BRCA1 and Breast Cancer: a Review of the Underlying Mechanisms Resulting in the Tissue-Specific Tumorigenesis in Mutation Carriers

Abstract

Since the first cloning of BRCA1 in 1994, many of its cellular interactions have been elucidated. However, its highly specific role in tumorigenesis in the breast tissue—carriers of BRCA1 mutations are predisposed to life-time risks of up to 80%—relative to many other tissues that remain unaffected, has not yet been fully enlightened. In this article, we have applied a universal model of tissue-specificity of cancer genes to BRCA1 and present a systematic review of proposed concepts classified into 4 categories. Firstly, tissue-specific differences in levels of BRCA1 expression and secondly differences in expression of proteins with redundant functions are outlined. Thirdly, cell-type specific interactions of BRCA1 are presented: its regulation of aromatase, its interaction with Progesterone- and receptor activator of nuclear factor-κB ligand-signaling that controls proliferation of luminal progenitor cells, and its influence on cell differentiation via modulation of the key regulators jagged 1-NOTCH and snail family transcriptional repressor 2. Fourthly, factors specific to the cell-type as well as the environment of the breast tissue are elucidated: distinct frequency of losses of heterozygosity, interaction with X inactivation specific transcript RNA, estrogen-dependent induction of genotoxic metabolites and nuclear factor (erythroid-derived 2)-like 2, and regulation of sirtuin 1. In conclusion, the impact of these concepts on the formation of hormone-sensitive and -insensitive breast tumors is outlined.

BRCA1 mutation influences progesterone response in human benign mammary organoids

“…Notch signaling has been implicated in the regulation of stem and progenitor cell fate determination as well as cell survival and proliferation [40]. The Notch signaling pathway interacts with BRCA1 in the breast via transcriptional upregulation of jagged 1 (JAG1) and regulates breast differentiation [41]. Our RNA-seq data revealed that Notch signaling was differentially regulated between non-carrier and BRCA1 mut organoids in response to hormones (Additional file 6: Figure S6).…”

Tumor antigens heterogeneity and immune response-targeting neoantigens in breast cancer

“…Breast cancer is both the most common type of cancer and the most frequent cause of cancer mortality in women [1], with a global burden of 2 088 849 new cases (11.6% of all new cancer cases) and 626 679 deaths (6.6% of all cancer deaths) in 2018 [2]. The most common presentation of breast cancer is invasive ductal carcinoma (50%-75% of patients), in which cancer cells spread from the milk duct into the periductal fibrous or fatty tissue, followed by invasive lobular carcinoma (5%-15% of patients), in which cancer cells originate from the milk-producing breast lobules and spread to the surrounding tissues and towards the duct.…”

“…In addition to the oncogenic mechanisms highlighted by the HR/ERBB2/TNBC classification, another significant element of risk for the neoplastic conversion of normal mammary cells is the presence of inheritable mutations in various genes (BRCA1, BRCA2, TP53, PTEN, ATM, CHEK2, and HRAS1), which is evidenced by family pedigrees and a history of the specific neoplasm in a first-degree relative with a history of breast cancer [1]; however, inheritable patterns only characterize 20%-25% of all affected families, and their etiological contribution to carcinogenesis remains the subject of investigation [1].…”

From Ocean to Medicine: Pharmaceutical Applications of Metabolites from Marine Bacteria

“…Genetic factors can play an important part in the appearance of cancerous formations. This is the case of breast cancer and the tumour suppressing gene, BRCA1 , as carriers are predisposed to life-time risks of up to 80% [ 34 ]. Furthermore, environmental factors, such as tobacco smoking, increase in urban pollution, increased intake of high caloric foods and longer lifespans all contribute to increasing the risk of cancer diagnosis [ 35 ].…”